RS50737B - BETA-AMINO TETRAHYDROIMIDASE (1,2-A) PYRAZINES AND TETRAHYDROTRIAZOLO (4,3-A) PYRAZINES AS DIPEPTIDYL PEPTIDASE INHIBITORS IN THE TREATMENT OR PREVENTION OF DIABETES - Google Patents

Abstract

Compound of Formula I: wherein: Ar is phenyl which is unsubstituted or substituted with 1-5 R3, wherein R3 is independently selected from the group consisting of: (1) halogen, (2) C1-6alkyl, which is linear or garnet and unsubstituted or substituted with 1-5 halogens, (3) OC1-6alkyl, which is linear or garnet and unsubstituted or substituted with 1-5 halogens, and (4) CN; X is selected from the group consisting of: (l) N , and (2) CR2; R1 and R2 are independently selected from the group consisting of: (1) hydrogen, (2) CN, (3) C1-10alkyl, which is linear or garnet and which is unsubstituted or substituted by 1-5 halogen, or phenyl, which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C1-6alkyl, wherein CO2C1-6alkyl is linear or garnet, (4 ) phenyl which is unsubstituted or substituted by 1-5 substituents independently selected from halogen, CN, OH, R4, OR4, NHSO2R4, SO2R4, CO2H and CO2C1-6alkyl, wherein CO2C1-6alkyl is linear or garnet, and (5 ) 5- or 6-membered heterocycle. which may be saturated or unsaturated and containing 1-4 heteroatoms independently selected from N, S and O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, C1-6alkyl and OC1-6alkyl , wherein C1-6alkyl and OC1-6alkyl are linear or garnets and optionally substituted with 1-5 halogens; R4 is C1-6alkyl, which is linear or garnet and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO2H and CO2C1-6alkyl, wherein CO2C1-6alkyl is linear or garnet; and its pharmaceutically acceptable salts and individual diastereomers. The application contains another 29 dependent claims.

Description

STATE OF THE ART

Diabetes refers to the course of the disease, which originates from multiple causative factors and is marked by elevated plasma glucose levels or hyperglycemia in the fasting state or after the administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often, abnormal glucose homeostasis is associated both directly and indirectly with changes in lipid, lipoprotein, and apolipoprotein metabolism and other metabolic and hemodynamic diseases. Therefore, patients with type 2 diabetes mellitus are at a particularly increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease. hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism and hypertension... is crucially important in the clinical management and treatment of diabetes mellitus.

There are two commonly recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to non-diabetics; however, these patients have developed resistance to insulin's stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues: muscle, liver, and adipose tissue, and plasma insulin levels, despite being elevated, are not sufficient to overcome marked insulin resistance.

Insulin resistance is not primarily due to a reduced number of insulin receptors, but to a defect in post-insulin binding to the receptor, which has not yet been elucidated. This resistance to the insulin response leads to insufficient insulin activation of glucose consumption, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and glucose production and secretion in the liver.

Current models of type 2 diabetes, which have not changed significantly over many years, have recognizable limitations. While physical exercise and reduction of food calories will dramatically improve the condition of diabetes, the effect of this treatment is very weak due to a sedentary lifestyle and excessive food intake, especially food that contains high amounts of saturated fat. Increasing plasma insulin levels by administering sulfonylureas (e.g., tolbutamide and glipizide) or meglitinides, which stimulate pancreatic (3-cells to secrete more insulin, and/or by injecting insulin, when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate highly insulin-resistant tissues. However, dangerously low levels can occur when insulin or insulin secretagogues (sulfonylureas or meglitinides) are administered. plasma glucose, and increased insulin resistance can occur due to even higher plasma levels of insulin. Biguanides lead to some correction of hyperglycemia. However, two biguanides, phenformin, can produce lactic acidosis and nausea/diarrhea. Metformin is often prescribed for the treatment of type 2 diabetes.

Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a recently described group of compounds with the potential to improve many symptoms of type 2 diabetes. These agents significantly increase insulin sensitivity in muscle, liver, and adipose tissue in several animal models of type 2 diabetes, leading to partial or complete correction of elevated plasma glucose levels without hypoglycemia. The currently marketed glitazones are peroxisomal proliferator-activated receptor (PPAR) agonists, receiving the PPAR-gamma subtype. It is generally believed that the PPAR-gamma agonist effect is responsible for the improved insulin sensitivity observed with glitazones. Newer PPAR agonists, which have been tested for the treatment of type II diabetes, are agonists of the alpha, gamma, or delta subtypes or a combination of these and in many cases are chemically different from glitazones (ie, they are not thiazolidinediones). Serious side effects (eg, liver toxicity) have occurred with some of the glitazones, such as troglitazone.

Other treatments for the disease are still being researched. New biochemical approaches, recently introduced or still in development, include treatment with alpha-glucosidase inhibitors (eg, acarbose) and with protein tyrosine phosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the enzyme dipeptidyl peptidase-IV ("DP-IV" or "DPP-IV") are also being investigated as drugs that may be useful in the treatment of diabetes, particularly type II diabetes. See, for example, WO 97/40832, WO 98/19998, U.S. Patent No. 5,939,560, Bioorg. Med. Chem. Lett., 6(10), 1163-1166 (1996); iBioorg. Med. Chem. Lett., 6(22), 2745-2748

(1996). The utility of DP-IV inhibitors in the treatment of type II diabetes is based on the fact that DP-IV in vivo inactivates glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are incretins and are produced when food is consumed. Incretins stimulate insulin production. Inhibition of DP-IV leads to reduced inactivation of incretins, and this, in turn, increases the effectiveness of incretins in stimulating insulin production by the pancreas. DP-IV inhibition thus leads to increased serum insulin levels. Conveniently, since the body produces incretins only when food is ingested, DP-IV inhibition is not expected to increase insulin levels at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycemia). Therefore, DP-IV inhibition is expected to increase insulin without increasing the risk of hypoglycemia, a dangerous side effect associated with the use of insulin secretagogues.

DP-IV inhibitors also have other therapeutic uses, as discussed herein. DP-IV inhibitors have not been widely studied to date, especially not for non-diabetic uses. New compounds are needed so that improved DP-IV inhibitors may be found in the treatment of diabetes and possibly other diseases and conditions.

EXPOSITION OF THE ESSENCE OF THE INVENTION

The present invention is directed to compounds which are inhibitors of the enzyme dipeptidyl peptidase-IV ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the enzyme dipeptidyl peptidase-IV is involved, such as diabetes, and in particular type 2 diabetes. The invention is particularly directed to pharmaceutical mixtures containing these compounds, as well as to the use of these compounds and mixtures in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds of formula I:

in which:

Ar is phenyl, which is unsubstituted or substituted with 1-5 substituents R<3>, wherein R<3> is independently selected from the group consisting of:

(1) halogen,

(2) C 1-6 alkyl, which is straight chain or branched and unsubstituted or substituted with 1-5 halogens, (3) OC 1-6 alkyl, which is straight chain or branched and unsubstituted or substituted with 1-5 halogens, and (4) CN;

X is selected from the group consisting of:

(1) N and

(2) CR<2>;

R<1> and R<2> are independently selected from the group consisting of:

(1) hydrogen,

(2) CN,

(3). CC^C^alkyl straight chain or branched chain, (4) phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R<4>, OR<4>, NHS02R<4>, SO2R<4>, 0O2H and COgC^alkyl, where COgC^alkyl is straight chain or branched and (6) 5- or A 6-membered heterocycle, which can be saturated or unsaturated, and contains 1-4 heteroatoms independently selected from: N, S and O; heterocycle, which is unsubstituted or substituted with 1-3 substituents independently selected from: oxo, OH, halogen, C 1-6 alkyl and OC 1-6 alkyl, where C 1-6 alkyl and OC 1-6 alkyl are straight chain or branched and optionally substituted with 1-5 halogens;

R<4> is C 1-4 alkyl, which is straight chain or branched chain and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO 2 H and CO 2 alkyl, where CO 2 alkyl is straight or branched chain;

and their pharmaceutically acceptable salts and individual diastereomers thereof.

An embodiment of the present invention includes compounds of formula Ia:

wherein: X, Ar and R<1> are as defined herein;

and their pharmaceutically acceptable salts and individual diastereomers.

Another embodiment of the present invention includes compounds of formula lb:

wherein Ar and R<1> are as defined herein;

and their pharmaceutically acceptable salts and individual diastereomers.

Another embodiment of the present invention includes compounds of formula Ic:

in which: Ar, R<1> and R<2> are defined here:

and their pharmaceutically acceptable salts and individual diastereomers thereof.

In this invention, it is preferred that Ar is phenyl, which is unsubstituted and substituted with 1-5 substituents, which are independently selected from the group consisting of:

(1) fluorine,

(2) bromine and

(3) CF3.

In the present invention, it is preferred that Ar is selected from the group consisting of:

(1) phenyl,

(2) 2-fluorophenyl,

(3) 3,4-difluorophenyl,

(4) 2,5-difluorophenyl,

(5) 2,4,5-trifluorophenyl

(6) 2-fluoro-4-(trifluoromethyl)phenyl and

(7) 4-bromo-2,5-difluorophenyl.

In this invention, it is preferred that R<1> is selected from the group consisting of:

(1) hydrogen and

(2) C 1-6 alkyl, which is straight or branched chain and which is unsubstituted or substituted with phenyl or 1-5 fluoro.

In the present invention, it is preferred that R<1> is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) CF3,

(5) CH2CF31

(6) pheniia and

(7) benzyl.

In the present invention, it is preferred that R<1> is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) CF3i

(5) CH2CF3.

In the present invention, it is even more preferred that R<1> is hydrogen or CF3.

In the present invention, it is preferred that R 2 is selected from:

(1) hydrogen,

(2) C 1-6 alkyl, which is straight chain or branched and which is unsubstituted or substituted with 1-5 fluoro, (3) phenyl, which is unsubstituted or substituted with 1-3 substituents, independently selected from: fluoro, OCH 3 and OCF 3 .

In the present invention, it is preferred that R<2> is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) ethyl,

(4) CF3,

(5) CH2CF3,

(5) CF2CF3,

(6) phenyl,

(7) (4-methoxy)phenyl,

(8) (4-trifluoromethoxy)phenyl,

(9) 4-fluorophenyl,

(10) 3,4-difluorophenyl.

In the present invention, it is even more preferred that R<2> is CF 3 or CF 2 F 3 .

In the present invention, it is preferred that R<3> is F, Br or CF3.

The compounds of this invention may have one or more asymmetric centers and therefore may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and single diastereomers. The compounds of this invention have one asymmetric center on the beta carbon atom. Additional asymmetric centers may be present depending on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds be encompassed within the scope of this invention. All such isomeric forms of these compounds are intended to be encompassed by this invention.

Some of the compounds described herein contain olefinic double bonds and, unless otherwise indicated, are meant to include both E and Z geometric isomers.

Some of the compounds described herein may exist as tautomers, having different hydrogen bonding points followed by one or more changes in double bonds. For example, a ketone and its enol form are keto-enol tautomers. Individual tautomers, as well as mixtures thereof, are encompassed by the compounds of this invention.

Formula I shows the structure of a group of compounds without preferred stereochemistry. Formula Ia shows the preferred stereochemistry at the carbon atom attached to the amine group of the beta amino acid from which these compounds are prepared.

Independent syntheses of these diastereomers or their chromatographic separations can, as is known in the art, be achieved by appropriate modification of the methodology set forth herein. Their absolute stereochemistry can be determined by x-ray crystallography of crystalline products or crystalline intermediates derived, if necessary, with reagents containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of compounds can be resolved to separate the individual enantiomers. Separation can be accomplished by methods well known in the art, such as coupling a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, and then separating the individual diastereomers by standard methods, such as fractional crystallization or chromatography. Often the coupling reaction is the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivatives can then be converted to pure enantiomers by cleaving the added chiral residue. A racemic mixture of compounds can also be separated directly by chromatographic procedures, which are well known in the art, using a chiral stationary phase.

Alternatively, either enantiomer of the compound may be obtained by stereoselective synthesis, using optically pure starting materials or reagents of known configuration, by methods well known in the art.

The term "pharmaceutically acceptable salts" refers to salts produced from pharmaceutically acceptable non-toxic bases or acids, which include inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include: aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts in solid form can exist in more than one crystal structure and can also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and ion exchange resin bases, such as: arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include: acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, amber, sulfuric, tartaric, p-toluenesulfonic and so on. Particularly preferred are: citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

It will be understood that, as used herein, the references to compounds of Formula I are also intended to include pharmaceutically acceptable salts.

As will be understood by those skilled in the art, halo or halogen, as used herein, includes: fluoro, chloro, bromo, and iodo. Similarly, C₁, as in C₁alkyl, is defined to designate groups with: 1, 2, 3, 4, 5, 6, 7 or 8 carbons in a straight or branched chain arrangement, so C₁alkyl specifically includes: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl. Similarly, C0, as in C0alkyl, is intended to indicate the presence of a direct covalent bond. A group designated as independently substituted with substituents may be independently substituted with multiple such substituents. The term "heterocycle" as used herein is intended to include 5- or 6-membered ring systems, which are within the following list: benzimidazolyl, benzodioxanyl, benzofuranyl, benzopyrazolyl, benzothiadiazoiii, benzotriazolyl, benzothiophenyl, benzoxadiazolyl, benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl!, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydroimidazolyl, tetrahydroisoquinolinyl and tetrahydrothienyl.

Exemplifying the invention is the use of the compounds disclosed in the Examples and herein.

Particular compounds within the scope of this invention include a compound selected from the group consisting of the compounds set forth in the following Examples and their pharmaceutically acceptable salts and individual diastereomers thereof.

The subject compounds are useful in a method of inhibiting the dipeptidyl peptidase-IV enzyme in a patient, such as a mammal in need of such inhibition, which comprises administering an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as inhibitors of dipeptidyl peptidase-IV enzyme activity.

In addition to primates, such as humans, various other mammals may be treated according to the method of the present invention. For example, mammals can be treated, including but not limited to: cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, or other bovine, ovine, equine, canine, feline, rodent, or murine species. However, the procedure can also be carried out in other species, such as avian species (eg, chickens).

The present invention is further directed to a method of producing a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity in humans and animals, which comprises combining a compound of the present invention with a pharmaceutical carrier or diluent.

The subject of treatment in these procedures is, in general, a mammal, preferably a human, male or female, in which inhibition of dipeptidyl peptidase-IV enzyme activity is desired. The term "therapeutically effective amount" means an amount of a subject compound that will elicit a biological or medical response in a tissue, system, animal or human organism, as sought by an investigator, veterinarian, physician or other clinician.

The term "mixture", as used herein, includes a product containing specific ingredients in specific amounts, as well as any product resulting, directly or indirectly, from a combination of specific ingredients in specific amounts. Such term, in connection with a pharmaceutical mixture, shall include the product, which includes the active ingredient(s) and the inert ingredient(s) constituting the carrier, as well as any product resulting, directly or indirectly, from the joining, complexing or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that the carrier, diluent or carrier must be compatible with the other ingredients of the formulation and cannot be harmful to their recipient.

The terms "administering" and "administering" a compound are to be understood as providing a compound of the invention or a prodrug of a compound of the invention to an individual in need of treatment.

The utility of the compounds of the present invention as inhibitors of dipeptidyl peptidase-IV enzyme activity can be demonstrated by methodology known in the art. The inhibition constants are determined as follows. A continuous fluorimetric assay is used with the substrate Gly-Pro-AMC of a DP-IV cap which releases the fluorescent AMC leaving group. The kinetic parameters describing this reaction are as follows: Km= 50 u.M; k^= 75 s"<1>; kca/<K>m= 1.5 x 10<6>M'V. A typical reaction contains approximately 50 pM enzyme, 50 uM Gly-Pro-AMC and buffer (100 mMHEPES, pH 7.5, 0.1 mg/ml 3 SA) in a total reaction volume of 100 µl. The release of AMC is continuously monitored in a plate fluorometer with 96 reaction sites using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Under these conditions, approximately 0.8U.M of AMC is produced over 30 minutes at 25 degrees C. The enzyme used in these studies was a soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression system (Bac-To-Bac, Gibco). BRL).The kinetic constants for hydrolysis were found to be Glv-Pro-AMC and GLP-1 in accordance with literature values for the native enzyme. In order to measure dissociation constants for compounds, inhibitor solutions in DMSO are added to reactions containing enzyme and substrate (final DMSO concentration is 1%). All experiments were performed at room temperature, using the standard reaction conditions described above. To determine dissociation constants (Ki), reaction rates were fitted by non-linear regression of the Michaelis-Menton equation for competitive inhibition. Errors in reproducing the dissociation constants are usually less than a factor of two.

More specifically, the compounds of the following examples had dipeptidyl peptidase-IV inhibitory activity in the above assays, generally with IC values of less than about 1 µM. This result is indicative of significant activity of the compound when used as an inhibitor of dipeptidyl peptidase-IV enzyme activity.

The enzyme dipeptidyl peptidase-IV (DP-IV) is a cell surface protein, which is involved in a wide range of biological functions. It has a wide tissue distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum) and distinct tissue and cell type expression levels. DP-IV is identical to the CD26 marker of T cell activation and can cleave numerous immunoregulatory, endocrine and neurological peptides in vitro. This has suggested a potential role for this peptidase in various disease processes in humans and other species.

Accordingly, the subject compounds are useful in the prevention or treatment of the following diseases, disorders and conditions.

Type II diabetes and related disorders: It has already been established that the incretins GLP-1 and GIP are rapidly inactivated in vivo by DP-IV. Studies with DP-IV<<>"<A>)-deficient mice and preliminary clinical studies indicate that DP-IV inhibition increases steady-state concentrations of GLP-1 and GIP leading to improved glucose tolerance. Analogous to GLP-1 and GIP, other peptides of the glucagon family, which are involved in glucose regulation, also appear to be inactivated by DP-IV (eg, PACAP, glucagon). Inactivation of these peptides by DP-IV may also play a role in glucose homeostasis.

The DP-IV inhibitors of the present invention are therefore useful in the treatment of type II diabetes, including: metabolic syndrome X, reactive hypoglycemia and diabetic dyslipidemia. Obesity, discussed below, is another condition often found with type II diabetes that may respond to treatment with compounds of the present invention.

The following diseases, disorders and conditions are related to type II diabetes and therefore can be treated, controlled or in some cases prevented by treatment with the compounds of the present invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic ovary syndrome) and other disorders that have a component of insulin resistance.

Obesity: DP-IV inhibitors may be useful in the treatment of obesity. This is based on the observed inhibitory effects on food intake and gastric emptying of GLP-1 and GIP. Exogenous administration of GLP-1 in humans significantly reduces food intake and slows gastric emptying (Am. J. Phvsiol. 277, R910-R916 (1999)). ICV administration of GLP-1 in rats and mice also has profound effects on food intake (Nature Medicine 2, 1254-1258 (1996)). This inhibition of feeding is not observed in GLP-1 R("/_) mice, indicating that these effects are mediated through GLP-1 receptors in the brain. Analogous to GLP-1, GLP-2 also appears to be regulated via DP-IV. ICV administration of GLP-2 also inhibits food intake, analogous to the effects observed with GLP-1 (Nature Medicine 6, 802-807

(2000)).

Growth hormone deficiency: Inhibition of DP-IV may be useful for the treatment of growth hormone deficiency, which is based on the hypothesis that growth hormone-releasing factor (GRF), a peptide that stimulates the release of growth hormone from the anterior pituitary, is cleaved by the enzyme DP-IVinvivo(W0 00/56297). The following data provide evidence that GRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitro to generate the inactive product GRF[3-44] (BBA 1122, 147-153 (1992)); (2) GRF is rapidly degraded in plasma to GRF[3-44]; this is prevented by the DP-IV inhibitor diprotin A; and (3) GRF[3-44] is found in the plasma of transgenic pigs with human GRF (J. Clin. Invest. 83, 1533-1540 (1989)). Therefore, DP-IV inhibitors may be useful for the same range of indications considered for growth hormone secretagogues.

Intestinal injury: The possibility of using DP-IV inhibitors in the treatment of intestinal injury was suggested by the results of studies indicating that glucagon-like peptide-2 (GLP-2), an apparently endogenous substrate for DP-IV, can exert a trophic effect on the intestinal epithelium (Regulator/Peptides 90, 27-32 (2000)). Administration of GLP-2 increases rodent small intestinal mass and reduces intestinal injury in rodent models of colitis and enteritis.

Immunosuppression: DP-IV inhibition may be useful in modulating the immune response, based on studies that have implicated the DP-IV enzyme in T cell activation and chemokine production, as well as studies of the efficacy of DP-IV inhibitors in in vivo disease models. DP-IV was shown to be identical to CD26, a cell surface marker for immune cell activation. CD26 expression is regulated by the differentiation and activation status of immune cells. It is generally accepted that CD26 functions as a co-stimulatory molecule in in vitro models of T cell activation. A number of chemokines contain proline in the penultimate position, presumably to protect them from degradation by non-specific amino-peptidases. Many of these were shown to undergo DP-IV in vitro. In several cases (RANTES, LD78-beta, MDC, eotaxin, SDF-1alpha), cleavage resulted in a burst of activity in chemotaxis and signaling assays. Receptor selectivity also appears to be modified in some cases (RANTES). Multiple N-terminally truncated forms of numerous chemokines, including predictable products of DP-IV hydrolysis, have been identified in in vitro cell culture systems.

DP-IV inhibitors have been shown to be effective immunosuppressants in animal models of transplantation and arthritis. Prodipine, (Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DP-IV, has been shown to double the survival of rat cardiac allografts from day 7 to day 14 (Transplantation 63, 1495-1500 (1997)). DP-IV inhibitors were tested in collagen- and alkyldiamine-induced arthritis in rats and showed statistically significant attenuation of hindpaw swelling in this model (Int. J. Immunopharmacologv 19, 15-24 (1997), Immunopharmacologv 40, 21-26 (1998)). DP-IV is upregulated in a number of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, Graves' disease, and Hashimoto's thyroiditis (Immunologv Today 20, 367-375 (1999)).

HIV infection: Inhibition of DP-IV may be useful in the treatment or prevention of HIV infection or AIDS because a number of chemokines, which inhibit HIV entry into the cell, are potential substrates for DP-IV (immunology Today 20, 367-375 (1999)). In the case of SDF-1alpha, cleavage reduces antiviral activity (PNAS95, 6331-6 (1998)). Therefore, the stabilization of SDF-1alpha through the inhibition of DP-IV is expected to reduce the infectivity of HlV.

Hematopoiesis: Inhibition of DP-IV may be useful in the treatment or prevention of hematopoiesis, as DP-IV may be involved in hematopoiesis. The DP-IV inhibitor, Val-Boro-Pro, stimulated hematopoiesis in a mouse model of cyclophosphamide-induced neutropenia (WO 99/56753).

Neuronal Disorders: Inhibition of DP-IV may be useful in the treatment or prevention of various neuronal or psychiatric disorders because numerous peptides involved in a variety of neuronal processes are cleaved in vitro by DP-IV. A DP-IV inhibitor may therefore be of therapeutic benefit in the treatment of neuronal disorders. Endomorphin-2, beta-casomorphin and substance Pin have been shown to be in vitro substrates for DP-IV. In all cases, in vitro cleavage is highly efficient, with kca/Km~10<6>M"V<1> or greater. In a test model of electric shock jump analgesia in rats, a DP-IV inhibitor showed a significant effect that was independent of the presence of exogenous endomorphin-2 (Brain Research 815, 278-286 (1999)).

Tumor invasion and metastasis: Inhibition of DP-IV may be useful in the treatment or prevention of tumor invasion and metastasis because increased or decreased expression of several ectopeptidases, including DP-IV, has been observed during the transformation of normal cells into malignant phenotypes (J. Exp. Med. 190, 301-305 (1999)). The up- or down-regulation of these proteins appears to be tissue-specific and cell-type-specific. for example, T cell lymphoma, T cell acute lymphoblastic leukemia, thyroid carcinomas of cellular origin, basal cell carcinomas, and breast carcinomas all show increased expression of CD26/DP-IV, so DP-IV inhibitors may be useful in the treatment of such cancers.

Benign prostatic hypertrophy: Inhibition of DP-IV may be useful in the treatment of benign prostatic hypertrophy because increased DP-IV activity has been observed in prostate tissue of patients with BPH (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)).

Sperm Motility/Male Contraception: Inhibition of DP-IV may be useful in altering sperm motility and for male contraception, as seminal fluid, prostatosomes, prostate-derived organelles important for sperm motility, possess very high levels of DP-IV activity (Eur. J. Clin. Chem. Clin. Biochem 30, 333-338 (1992)).

Gingivitis: Inhibition of DP-IV may be useful in the treatment of gingivitis because DP-IV activity has been found in gingival cervical fluid and has been correlated with the severity of periodontal disease in some studies (Arch. Oral Biol. 37, 167-173 (1992)).

Osteoporosis: Inhibition of DP-IV may be useful in the treatment or prevention of osteoporosis because GIP receptors are present in osteoblasts.

The compounds of the present invention are useful in the treatment or prevention of one or more of the following conditions or diseases: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) fat disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarian hyperandrogenism (polycystic syndrome ovaries), (25) type II diabetes, (26) growth hormone deficiency, (27) neutropenia, (28) neuronal disorders, (29) tumor metastasis, (30) benign prostatic hypertrophy, (32) gingivitis, (33) hypertension, (34) osteoporosis and other conditions that can be treated or prevented by DP-IV inhibition.

The compounds discussed are further useful in the prevention or treatment of the aforementioned diseases, disorders and conditions in combination with other agents.

The compounds of the present invention may be useful in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions in which the compounds of Formula I or other drugs may be useful, where the combination of drugs administered together is safer or more effective than either drug when administered alone. Such other drug(s) may be administered by its usual route and in its usual amount, simultaneously with or immediately after the compound of Formula I. When the compound of Formula I is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs and the compound of Formula I in unit dose form is preferred. However, combination therapy may also include therapies in which a compound of Formula I and one or more other drugs are administered on various overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used at lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more active ingredients in addition to a compound of Formula I.

Examples of other active ingredients that may be administered in combination with a compound of Formula I and whether administered separately or in the same pharmaceutical composition include, but are not limited to: (a) other dipeptidyl peptidase-IV (DP-IV) inhibitors; (b) insulin sensitizers, which include: (i) PPARy agonists, such as glitazones (eg, troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, etc.) and other PPAR ligands, including PPARot/y dual agonists, such as KRP-297 and PPARa agonists, such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate, and benzafibrate), (ii) biguanides, such as are metformin and phenformin and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylureas and other insulin secretagogues, such as tolbutamide and glipizide, meglitinide and related materials; (e) α-glucosidase inhibitors (such as acarbose); (f) glucagon receptor antagonists, such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810; (g) GLP-1, GLP-1 mimetics and GLP-1 receptor agonists, such as those disclosed in WO 00/42026 and WO 00/59887; (h) GIP and GIP mimetics, such as those disclosed in WO 00/58360 and GIP receptor agonists; (i) PACAP, PACAP mimetics and PACAP receptor 3 agonists, such as those disclosed in WO 01/23420; (j) cholesterol-lowering agents, such as: (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin and other statins), (ii) sequestrants (cholestyramine, colestipol and dialkylaminoalkyl derivatives of cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or its salt, (iv) PPARct agonists, such as phenonic acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (v) PPARa/y dual agonists, such as KRP-297, (vi) cholesterol absorption inhibitors, such as beta-sitosterol and ezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors, such as avasimibe and (viii) antioxidants, such as probucol; (k) PPAR5 agonists, such as those disclosed in VV097/28149; (I) anti-obesity compounds, such as: fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors and 33 adrenergic receptor agonists;

(m) ileal bile acid transporter inhibitor; and

(n) agents used in inflammatory conditions, such as: aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine and cyclooxygenase-2 selective inhibitors.

The above combinations include combinations of compounds of the present invention not only with one other active compound but also with two or more other active compounds. Non-limiting examples include combinations of compounds of Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DP-IV inhibitors, and anti-obesity compounds.

Similarly, the compounds of the present invention may be used in combination with other compounds used in the treatment/prevention/suppression or amelioration of diseases or conditions for which the compounds of the present invention are useful. Such other drugs can be administered by the route and in the amount in which they are usually used, simultaneously with or immediately after the compounds of this invention. When a compound of the present invention is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs together with the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those which also contain one or more other active ingredients in addition to the compounds of the present invention.

The weight ratio of the compound of the present invention to the other active ingredient can vary and will depend on the effective dosage of each ingredient. In general, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the second agent will generally be in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of compounds of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations, the compound of the present invention and other active agents may be administered separately or together. Furthermore, the application of one element may precede, be simultaneous with, or be immediately after the application of another agent(s).

The compounds of the present invention may be administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations, containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles suitable for every method of application. In addition to the treatment of warm-blooded animals, such as: mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of this invention are effective for use in humans.

Pharmaceutical mixtures for the administration of the compounds of the present invention can simply be presented in the form of a dosage unit and can be produced by any of the methods well known in pharmaceutical practice. All methods include the step of bringing the active ingredient into contact with the carrier, which constitutes one or more additional ingredients. In general, pharmaceutical compositions are produced by uniformly and intimately bringing the active ingredient into contact with a liquid carrier or a subtly divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. In a pharmaceutical composition, the active compound under consideration is included in an amount sufficient to produce the desired effect on the disease process or condition. As used herein, the term "mixture" is intended to include a product that contains specific ingredients in specific amounts, as well as a product that results, directly or indirectly, from a combination of specific ingredients in specific amounts.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, lozenges, candies, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Mixtures intended for oral use may be prepared according to any procedure known in the art for the production of pharmaceutical mixtures and such mixtures may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, colorants and preservatives, with the aim of providing pharmaceutically refined and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutical acceptable bases, which are suitable for the production of tablets. These bases can, for example, be: inert diluents, such as: calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrators, for example, corn starch or alginic acid; binding agents, for example: starch, gelatin or acacia; and lubricants, for example: magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide prolonged action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. They may also be coated using techniques described in U.S. Pat. Patents 4,256,108; 4,166,452; and 4,265,874 to form controlled release osmotic therapeutic tablets.

Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin; or as soft gelatin capsules in which the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain active materials in a mixture with substrates suitable for the production of aqueous suspensions. Such supports are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; dispersing agents or wetting agents can be naturally occurring phosphatides, for example lecithin or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example heptadecaethyleneoxyethanol or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydride, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweeteners, such as sucrose or saccharin.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil, such as liquid paraffin. Oil suspensions may contain a thickening agent, for example, beeswax, heavy paraffin or cetyl alcohol. Sweetening agents, such as those discussed above, may be added as well as flavoring agents to provide a pleasant oral preparation. These mixtures can be preserved by the addition of antioxidants, such as ascorbic acid.

Dispersible powders and granules, suitable for making aqueous suspensions by adding water, provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example, olive oil or peanut oil, or a mineral oil, for example, liquid paraffin or mixtures of these. Suitable emulsifying agents can be gums, which occur in nature, for example, acacia or tragacanth, phosphatides, which occur in nature, for example, soybeans, lecithin and esters or partial esters derived from fatty acids and hexitol anhydride, for example, sorbitan monooleate, as well as condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening agents and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives, and fragrance and color agents.

Pharmaceutical compositions may be in the form of sterile injectable aqueous or oily suspensions. This suspension may be formulated in accordance with known practice, using those suitable dispersing or wetting agents and suspending agents previously mentioned. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are: water, Ringer's solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils are commonly used as a dissolving or suspending medium. Any slightly fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Furthermore, fatty acids, such as oleic acid, find use in the manufacture of injectables.

The compounds of this invention can also be administered in the form of suppositories for rectal administration of the drug. These mixtures can be produced by mixing the drug with a suitable non-irritating carrier, which is solid at ordinary temperatures, but is liquid at rectal temperature and therefore melts in the rectum releasing the drug. Such materials are cocoa butter and polyethylene glycols.

For surface application, the following are used: creams, ointments, jellies, solutions or suspensions, etc., which contain the compounds of this invention.

(For the purposes of this application, topical application will include mouth rinses and throat rinses).

The pharmaceutical composition and method of the present invention may further include other therapeutically active compounds, as noted herein, which are commonly used in the treatment of the aforementioned pathological conditions.

In the treatment or prevention of conditions requiring inhibition of dipeptidyl peptidase-IV enzyme activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; better about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range, the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in tablet form with 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for symptomatic dose adjustment of the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

When treating or preventing diabetes mellitus and/or hyperglycemia or hypertriglyceridemia or other diseases for which the compounds of this invention are indicated, generally satisfactory results are obtained when the compounds of this invention are administered at a daily dosage of about 0.1 milligram to about 100 milligrams per kilogram of animal body weight, preferably given as a single daily dose or divided doses two to six times a day or in the form of delayed release. For most large mammals, the total daily dose is about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen can be adjusted to ensure optimal therapeutic response.

It will be understood, however, that the particular dosage level and frequency of administration may vary for any particular patient and will depend on a variety of factors, including the activity of the specific compound employed, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, route and timing of administration, rate of excretion, drug combination, severity of the particular condition, and the host undergoing therapy.

Several procedures for making the compounds of this invention are illustrated in the Schemes and Examples, which follow. The starting materials were prepared according to procedures known in the art or as disclosed herein.

The compounds of this invention can be prepared from beta amino acid intermediates, such as those of formula II and substituted heterocyclic intermediates, such as those of formula III, using standard conditions of peptide coupling followed by deprotection. The production of these intermediates is described in the following schemes. wherein Ar, X and R<1> are as previously defined and P is a suitable nitrogen protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl.

Compounds of formula II are commercially available, known in the literature, or can be readily prepared by a variety of procedures known to those skilled in the art. One common route is shown in Scheme 1. The acid 1_, which may be commercially available or readily produced from the appropriate amino acid using protection, for example, di-tertobutyl dicarbonate (for P=Boc), carbobenzyloxy chloride (for P=Cbz) or AA(9-fluorenylmethoxycarbonyloxy)succinimide (for P=Fmoc), is treated with isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine, and then diazomethane. The resulting diazoketone is then treated with silver benzoate in a solvent such as methanol or aqueous dioxane and can be subjected to sonication and then the procedure of Sewald et al., Synthesis, 837 (1997) to provide beta amino acid II. As those skilled in the art will appreciate, enantiomerically pure alpha amino acids 1_ can be used to make enantiomerically pure beta amino acids II. Alternative routes for these compounds can be found in the following reviews: E. Juaristi, Enantioselective Synthesis of ( 5- Amino Acids, Ed., Wiley-VCH, New York; 1997, Juaristi et al., Aldrichimica Acta, 27,3

(1994), Cole et al., Tetrahedron, 32, 9517 (1994).

Compounds III are commercially available, known in the literature, or can be readily produced by a variety of procedures known to those skilled in the art. One convenient procedure is shown in Scheme 2. The unsaturated derivative 2 is reduced, for example, by treatment with hydrogen gas and a catalyst such as palladium on carbon or platinum oxide in a solvent such as methanol or ethanol to provide Compound

III.

Intermediates 2 of Scheme 2 are themselves commercially available, known in the literature, or can be easily produced by a variety of procedures known to those skilled in the art. One such procedure, when X is CR<2> , is shown in Scheme 3. Aminopyrazine 3 is treated with a 2-haloketone, such as 2-bromoketone 4 in a solvent, such as methanol or ethanol, to provide intermediate 2a. Alternatively, for the preparation of intermediate 2a in which R<2>is H, instead of intermediate 4, 2-bromo-dimethylacetal 5 and a catalytic amount of acid, such as hydrochloric acid, can be used.

A convenient procedure for making intermediate 2b, where X is N, is shown in Scheme 4. Chloropyrazine 6 is treated with hydrazine to provide hydrazinopyrazine 7. Compound 7 can be condensed either with an orthoester such as triethyl orthoester 8 to give 2b, or with a carboxylic acid 9 in polyphosphoric acid, at elevated temperatures, to give 2b.

An alternative route for the preparation of Compound 11lb wherein X is N is shown in Scheme 5. Compound 12<_>is prepared according to the procedure outlined above, using dichloropyrazine 1_0 instead of chloropyrazine 6. Compound 12 is then subjected to catalytic hydrogenation using a catalyst, such as platinum oxide, to provide Compound lllb as its monohydrochloride salt.

Intermediates II and III were coupled under standard peptide coupling conditions, for example, using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), 1-hydroxybenzotriazole (HOBT), and a base, generally diisopropylethylamine, in a solvent, such as N,N-dimethylformamide (dmf) or dichloromethane, for 3 to 48 hours at ambient temperature to provide intermediate 13 as shown in Scheme 6. The protecting group is then removed with, for example, trifluoroacetic acid or methanolic hydrogen chloride in the case of the Boe group, to give the desired amine I. The product is purified from unwanted by-products, if necessary, by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel, as described by VV.C.Still et al.,J. Org. Chem., 43, 2923 (1978) or by HPLC. Compounds that have been purified by HPLC can be isolated as the corresponding salts. Purification of intermediates is achieved in the same way.

In some cases, intermediate 13 from the coupling reaction described in Scheme 6 may be further modified prior to deprotection, for example, by treatment of substituents on X or R<1>. These treatments may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions commonly known to those skilled in the art.

In some cases, the order of carrying out the previously mentioned reaction schemes can be changed to facilitate the reaction or to avoid undesired reaction products.

( 3/ ?)- 3- f( 1 J- dimethylethoxycarbonyl) amino1- 4-( 215- difluorophenyl) butane

acid

Step A."( RS \- N - C \, 1- dimethylethoxycarbonyl)- 2, 5- difluorophenylalanine

To a solution of 0.5 g (2.49 mmol) of 2,5-difluoro-DL-phenylalanine in 5 ml of ferrobutanol, 1.5 ml of 2N aqueous sodium hydroxide solution and 543 mg of di-tert-butyl dicarbonate were added. The reaction mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate. The organic phase was washed successively with 1N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 97:2:1 dichloromethane.methanol:acetic acid) to give 671 mg of the title compound. MS 302 (M+1).

Step B. (/ 9, S)- 3-[( 1, 1- dimethylethoxycarbonyl) amino]- 1- diazo- 4-( 2, 5-

difluorophenyl)butan-2-one

To a solution of 2.23 g (7.4 mmol) of (/^,S)-/N-(1,1-dimethylethoxycarbonyl!)-2,5-difluorophenylalanine in 100 ml_ of diethyl ether, at 0°C, 1.37 ml_ (8.1 mmol) of triethylamine and 0.931 ml_ (7.5 mmol) of isobutyl chloroformate were added in order and the reaction mixture was stirred at this temperature in for 15 minutes. Then, cooled ethereal solution of diazomethane was added until the yellow color persisted and stirring was continued for the next 16 h. Excess diazomethane was quenched by the dropwise addition of acetic acid and the reaction mixture was diluted with ethyl acetate and washed successively with 5% hydrochloric acid, saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 4:1 hexane:ethyl acetate) afforded 1.5 g of diazoketone. 1H NMR (500 MHz, CDCl3) δ 7.03-6.95 (m, 1H), 6.95-6.88 (m, 2H), 5.43 (bs, 1H), 5.18 (bs, 1H), 4.45 (bs, 1H), 3.19-3.12 (m, 1H), 2.97-2.80 (m, 1H), 1.38 (s, 9H).

Step C." (3^-3-Rl,1-dimethylethoxycarbonyl)amino]-4-(2.5-difluorophenyl)

butyric acid

3.3 mL (19 mmol) diisopropylethylamine and 302 mg (1.32 mmol) silver benzoate were added to a solution of 2.14 g (6.58 mmol) (/?,S)-3-[(1,1-dimethylethoxycarbonyl)-amino]-1-diazo-4-(2,5-difluorophenyl)butan-2-one dissolved in 100 mL methanol at -30°C. The reaction mixture was stirred for 90 min before diluting with ethyl acetate and washing sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and the enantiomers were separated by preparative chiral HPLC (ChiralpakAD column, 5% ethanol in hexanes) to give 550 mg of the desired (/T)-enantiomer, which eluted first. This material was dissolved in 50 mL of a mixture of tetrahydrofuran:methanol:1N aqueous lithium hydroxide (3:1:1) and stirred at 50°C for 4 h. The reaction mixture was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give 360 mg of the title compound as a foamy solid.<1>H NMR (500 MHz, CDCl3) 5 7.21 (m, 1H), 6.98 (m, 2H), 6.10 (bs, 1H), 5.05 (m, 1H), 4.21 (m. 1H), 2.98 (m, 2H), 2.60 (m, 2H), 1.38 (s, 9H).

( 3/^- 3- f( 1, 1- dimethylethoxycarbonyl) aminol4-[ 2- fluoro- 4-( trifluoromethyl) phenylbutanoic acid

Step A. (2/7,55)-2,5-dihydro-3,6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)-5-isopropylpyrazine

To a solution of 3.32 g (18 mmol) of commercially available (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 100 mL of tetrahydrofuran, at -70°C, was added 12 mL (19 mmol) of a 1.6 M solution of butyllithium in hexanes. After stirring at this temperature for 20 min, 5 g (19.5 mmol) of 2-fluoro-4-trifluoromethylbenzyl bromide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before warming the reaction mixture to ambient temperature. The reaction was quenched with water, concentrated in vacuo and extracted with ethyl acetate. The combined organic phase was washed with brine, dried and concentrated in vacuo. Purification by flash chromatography (silica gel, 0-5% ethyl acetate in hexanes) afforded 5.5 g of the title compound.<1>H NMR (500 MHz, CDCl3) 5 7.33-7.25 (m, 3H), 4.35-4.31 (m, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 3.60 (t, 1H, J=3.4 Hz), 3.33 (dd, 1H, J=4.6, 13.5 Hz), 3.03 (dd, 1H, J=7, 13.5 Hz), 2.25-2.15 (m, IH), 1.0 (d, 3H, J=7 Hz), 0.66 (d, 3H, J=7 Hz).

Step B. Methyl ester (/ T)- AA( 1, 1- dimethylethoxycarbonyl)- 2- fluoro- 4- trifluoromethyl)

phenylalanine

To a solution of 5.5 g (15 mmol) (2/?,5S)-2,5-dihydro-3,6-dimethoxy-2-(2'-fluoro-4'-(trifluoromethyl)benzyl)-5-isopropylpyrazine in 50 mL of a mixture of acetonitriquedichloromethane (10:1), 80 mL of 1N aqueous trifluoroacetic acid was added. The reaction mixture was stirred for 6 h and the organic solvents were removed in vacuo. Sodium carbonate was added until the solution became basic (>pH 8), then the reaction mixture was diluted with 100 mL of tetrahydrofuran and 10 g (46 mmol) of di-fe/c-butyldicarbonate was added. The resulting grainy mass was stirred for 16 h, concentrated in vacuo and extracted with ethyl acetate. The combined organic phase was washed with brine, dried and concentrated in vacuo. Purification by flash chromatography (silica gel, 20% ethyl acetate in hexanes) gave 5.1 g of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.38-7.28 (m, 3H), 5.10 (bd, 1H), 4.65-3.98 (m, 1H), 3.76 (s, 3H), 3.32-3.25 (m, 1H), 3J3-3.05 (m, 1H), 1.40 (s, 9H).

Step C. ( ff )- AA( 1, 1- dimethylethoxycarbonyl)- 2- fluoro- 4- trifluoromethyl) phenyl- alanine

A solution of 5.1 g (14 mmol) methyl ester of (/7,5)-AA(1,1-dimethylethoxycarbonyl)-2-fluoro-4-trifluoromethyl)phenylalanine in 350 mL of the mixture: tetrahydrofuran:methanol:1N lithium hydroxide (3:1:1) was stirred at 50°C for 4 h. The reaction mixture was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 4.8 g of the title compound. ^ NMR (500 MHz, CD3OD) δ 7.45-7.38 (m, 3H), 4.44-4.40 (m, 1H), 3.38-3.33 (m, 1H), 2.98 (dd, 1H, J=9.6, 13.5 Hz), 1.44 (s, 9H).

Step D. (3/9)-3-f"(1,1-dimethylethoxycarbonyl)amino]4-r2-fluoro-4-(trifluoromethyl)

Phenylbutyric acid

To a solution of 3.4 g (9.7 mmol) of the product from Step C in 60 mL of tetrahydrofuran, at 0°C, 2.3 mL (13 mmol) of diisopropylethylamine and 1.7 mL (13 mmol) of isobutyl chloroformate were added sequentially and the reaction mixture was stirred at this temperature for 30 minutes. A cooled ethereal solution of diazomethane was then added until the yellow color persisted and stirring was continued for another 16 h. Excess diazomethane was quenched by dropwise addition of acetic acid, and the reaction mixture was diluted with ethyl acetate and washed successively with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) produced 0.5 g of diazoketone. To a solution of 0.5 g (1.33 mmol) of diazoketone, dissolved in 100 mL of methanol, at 0°C, 0.7 mL (4 mmol) of diisopropylethylamine and 32 mg (0.13 mmol) of silver benzoate were added. The reaction mixture was stirred for 2 h before diluting with ethyl acetate and washing sequentially with: 2N hydrochloric acid, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo, dissolved in 50 mL of a mixture of tetrahydrofuran:methanol:1N aqueous lithium hydroxide (3:1:1) and stirred at 50°C for 3 h. The reaction mixture was cooled, acidified with 5% dilute hydrochloric acid and extracted with ethyl acetate. The organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 410 mg of the title compound as a white foamy solid. ?H NMR (500 MHz, CD3OD) δ 7.47-7.33 (m, 3H), 4.88 (bs, 1H), 4.26-3.98 (m, 1H), 3.06-3.01 (m, 1H), 2.33-2.77 (m, 1H), 2.58-2.50 (m, 2H), 1.29 (s, 9H).

(3/7)-3-f"(1,1-dimethylethoxycarbonyl)aminol-4-(2,4,5-trifluorophenyl)butanoic acid

Step A. ( 25, 5/ ?)- 2, 5- dihydro- 3, 6- dimethoxy- 2- isopropyl- 5-( 2'. 4', 5' trifluorobenzyl)-pyrazine

The title compound (3.81 g) was prepared from 3.42 g (18.5 mmol) of (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine, using the procedure described for Intermediate 2, Step A. <1>H NMR (500 MHz, CDCl3) 8-7.01 (m, 1H), 6.85 (m, 1H), 4.22 (m, 1H), 3.78 (m, 3H), 3.64 (m, 3H), 3.51 (m, 1H), 3.20 (m, 1H), 2.98 (m, 1H), 2.20 (m, 1H), 0.99 (d, 3H, J=8Hz), 0.62 (d, 3H, J=8Hz).

Step B. Methyl ester (^- AA( 1, 1- dimethylethoxycarbonyl)- 2, 4, 5- trifluorophenylalanine

To a solution of 3.81 g (11.6 mmol) of (2S,5/T)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(2',4',5'trifluoro-benzyl)pyrazine in 20 mL of acetonitrile was added 20 mL of 2N hydrochloric acid. The reaction mixture was stirred for 72 h and concentrated in vacuo. The residue was dissolved in 30 mL of dichloromethane and 10 mL (72 mmol) of triethylamine and 9.68 g (44.8 mmol) of di-fe/z>butyl dicarbonate was added. The reaction mixture was stirred for 16 h, diluted with ethyl acetate and washed successively with 1N hydrochloric acid and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) to give 2.41 g of the title compound. (m, 1H), 3.78 (m, 3H), 3.19 (m, 1H), 3.01 (m, 1H), 1.41 (s, 9H).

Step C. (/5)-/N-(1,1-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine

The title compound (2.01 g) was prepared from 2.41 g (7.5 mol) of (/t)-AA(1,1-dimethylethoxycarbonyl)-2,4,5-trifluorophenylalanine methyl ester, using the procedure described for Intermediate 2, Step C. MS (M+1)-BOC 220.9.

Step D. (3β)-3-F(1,1-dimethylethoxycarboniQamino1-4-(2,4,5-trifluorophenyl)-butanoic acid

To a solution of 0.37 g (1.16 mmol) (<y>^-AA(1,1<limethylethoxycarbonyl)-2,4,5-trifluorophenylalanine in 10 mL of diethyl ether, at -20°C, 0.193 mL (1.3 mmol) of triethylamine and 0.18 mL (1.3 mmol) of isobutyl chloroformate were added sequentially and the reaction mixture was stirred at this temperature for 15 minutes. A cooled ethereal solution of diazomethane was then added, and stirring was continued for another 1 h. The excess of diazomethane was quenched by dropwise addition of acetic acid, and the reaction mixture was diluted with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated in vacuo by chromatography (silica gel, 3:1 hexane.ethyl acetate) produced 0.36 g of diazoketone. 26 mg (0.113 mmol) of silver benzoate was added to a solution of 0.35 g (1.15 mmol) of diazoketone dissolved in 12 mL of 1,4-dioxane:water (5:1). The resulting solution was sonicated for 2 h before diluting with ethyl acetate, washing sequentially with 1N hydrochloric acid and brine, drying over magnesium sulfate, and concentrating in vacuo. Purification by flash chromatography (silica gel, 97:2:1 dichloromethane:methanol:acetic acid) gave 401 mg of the title compound.<1>H NMR (500 MHz, CDCL) δ 7.06 (m, 1H), 6.95 (m, 1H), 5.06 (bs, 1H), 4.18 (m, 1H), 2.98 (m, 2H), 2.61 (m, 2H), 1.39 (s, 9H),

( 3/ ?)- 3- r( 1, 1- dimethylethoxycarbonyl) amino1- 4-( 4- bromo- 2. 5- difluorophenyl)- butane

acid

Step A. 4-bromo-2,5-difluorobenzyl bromide

To a solution of 2 g (8.44 mmol) of 4-bromo-2,5-difluorobenzoic acid (prepared according to the procedure of lshikawa et al., Kogyo Kagaku Zasshi, p. 972-979, 1970) in 20 mL of tetrahydrofuran was added 40 mL of a 1 M solution of boron-tetrahydrofuran complex. The solution was heated under reflux for 64 h, cooled to room temperature and 100 mL of methanol was added. The reaction mixture was heated for the next 2 h, cooled and concentrated in vacuo. Purification by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) yielded 1.6 g of 4-bromo-2,5-difluorobenzyl alcohol. To a solution of 1.3 g (5.6 mmol) of 4-bromo-2,5-difluorobenzyl alcohol in 20 mL of dichloromethane, 2.27 g (6.7 mmol) of carbon tetrabromide and 1.8 g (6.7 mmol) of triphenylphosphine were added at 0°C. The reaction mixture was stirred for 2 h at this temperature, the solvent was removed in vacuo and the residue was mixed with 100 mL of diethyl ether. The solution was filtered, concentrated in vacuo and purified by flash chromatography (silica gel, 9:1 hexane:ethyl acetate) to give 1.5 g of the title compound.

Step B. (25,5/T)-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(4'-bromo-2',5'-

difluorobenzylpyrazine

The title compound (1.61 g) was prepared from 0.865 g (4.7 mmol) of (2S)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine and 1.5 g (5.2 mmol) of 4-bromo-2,5-difluorobenzyl bromide, using the procedure described for Intermediate 2, Step A.<1>H NMR (400 MHz, CDCl3) 8 7.21 (m, 1H), 6.97 (m, 1H), 4.25 (m, 1H), 3.78 (s, 3H), 3.70-3.64 (m, 4H), 3.25-3.18 (m, 1H), 2.96-2.90 (m, 1H), 2.25-2.16 (m, 1H), 1.01 (d, 3H, J=8Hz), 0.65 (d, 3H, J=8Hz).

Step C. Methyl Ester

phenylalanine

To a solution of 1.61 g (4.14 mmol) of (2S,5/^-2,5-dihydro-3,6-dimethoxy-2-isopropyl-5-(4'-bromo-2',5'-difluorobenzyl)pyrazine in 10 mL of acetonitrile was added 10 mL of 2N hydrochloric acid. The reaction mixture was stirred for 16 h and concentrated in vacuo. The residue was dissolved in 30 mL of dichloromethane and 5.6 mL (40 mmol) of di-tertobutyldicarbonate were added. The reaction mixture was stirred for 16 h, diluted with ethyl acetate and washed alternately with saturated aqueous sodium bicarbonate solution and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography (silica). gel, 9:1 hexanes; ethyl acetate) to give 1.22 g of the title compound. <1>H NMR (400 MHz, CDCl3) δ 7.27-7.15 (m, 1H), 6.98-6.93 (m, 1H), 5.08 (bs, 1H), 4.61-4.55 (m, 1H), 3.78 (s, 3H), 3.23-3.18 (m, 1H), 3.05-2.95 (m, 1H), 1.41 (s, 9H).

Step D. (/t)-/N-(1,1-dimethylethoxycarbonyl)-4-bromo-2,5-difluorophenylalanine

The title compound (1.34 g) was prepared from 1.4 g (3.5 mmol) of methyl ester (/5)-N-(1,1-dimethylethoxycarbonyl)-4-bromo-2,5-difluorophenylalanine using the procedure described for Intermediate 2, Step C. MS (M+1) 380.3 and 382.3.

Step E. (3/t)-3-R1,1-dimethylethoxycarbonyl)amino]-4-(4'-bromo-2',5'-difluoro-

Phenylbutanoic acid

The title compound (0.36 g) was prepared from 0.6 g (1.57 mmol)

(/t)-/N-(1,1-dimethylethoxycarbonyl)-4-bromo-2,5-difluorophenylalanine, using the procedure described for Intermediate 3, Step D. MS (M + 1) 394.1 and 396.1.

7- f( 3/^- 3- amino- 4-( 3, 4- difluorophenyl) butanoyl1- 2-( trifluoromethyl)- 5, 6, 7, 8-tetrahydroi midazof 1, 2- alpyrazine, dihydrochloride

Step A. 2-(Trifluoromethyl)imidazo[1,2-]pyrazine

- 1-bromo-3,3,3-trifluoroacetone (5.73 mL, 55.2 mmol) was added to a solution of 2-aminopyrazine (5.25 g, 55.2 mmol) in ethanol (120 mL). The reaction mixture was stirred at reflux for 20 h. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3x). The combined organic phase was washed with brine, . dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexane, then 100% ethyl acetate) to give 2.35 g of the title compound as a solid. <1>H NMR (500 MHz, CDCl3) δ 8.02 (m, 2H), 8.13 (m, 1H), 9.22 (s, 1H). ESI-MS 188 (M+1).

Step B. 2-(trifluoromethyl-5,6,7;8-tetrahydroimidazof 1,2-alpyrazine)

To a solution of 2-(trifluoromethyl)imidazo[1,2-a]pyrazine (2.0 g, 10.46 mmol, from Step A) in methanol (100 mL) was added 10% palladium on carbon (400 mg). The mixture was stirred under atmospheric hydrogen, at ambient temperature, for 14 h. The mixture was filtered through celite and washed with methanol (3X). The filtrate was concentrated and purified by flash chromatography

(silica gel, 10% methanol in ethyl acetate, then 15% methanol in chloroform with 1% aqueous ammonium hydroxide), to give 1.33 g of the title compound as a solid. (t, 2H, J=5.5Hz), 4.10 (S, 1H), 7.16 (S, 1H). ESI-MS 192 (M+1).

Step C. 7 -\{ 3R )- 3 -\{ 1, 1 - dimethylethoxycarboni]) amino1- 4-( 3, 4- difluorophenyl)

butanoyl- 2-( trifluoromethyl)- 5, 6, 7, 8- tetrahydroimidazo[ 1, 2- alpyrazine

To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3/t)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT. (54.5 mg, 0.42 mmol), at 0°C. The reaction mixture was stirred at 0°C for 10 min and then EDC (96.6 mg, 0.50 mmol) was added. After removing the ice bath, the reaction mixture was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as foamy solids. 1H NMR (500 MHz, CDCl 3 ) δ 1.36 (s, 9H), 2.62 (m, 2H), 2.86 (m, 2H), 3.34 (bs, 1H), 3.86 (m, 1H), 4.05 (m, 4H). 4.85 (m, 1H) 5.30-5.38 (m, 1H) 6.97 (m, 3H), 7.28 (m, 1H). LC/MS 489 (M+1).

Step D. 7-[( 3/ ?)- 3- amino- 4-( 3, 4- difluorophenyl) butanoyl1- 2-( trifluoromethyl)-5, 6, 7, 8- tetrahydroimidazo, 2- alpyrazine, dihydrochloride

7-[(3/c)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)

butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (110.8 mg, 0.226 mmol, from Step C) was added 2 mL of methanol, saturated with hydrogen chloride. The reaction mixture was stirred at ambient temperature

during 1 h. Concentration gave 89.5 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.97-3.10 (m, 4H), 3.91-4.34 (m, 5H), 4.90-5.04 (m, 2H), 7.16-7.33 (m, 2H), 8.01-8.08 (m, 1H). ESI-MS 389 (M+1).

7-|"( 3/ i)- 3- amino- 4-( 2, 5- difluorophenyl) butanoyl- 2-( trifluoromethyl)- 5, 6, 7. 8-tetrahydroimidazo f1, 2- alpyrazine, dihydrochloride

Step A.7 -\{ 3Ri - 3 -\{ 1, 1 - dimethylethoxycarbonyl) amino]- 4-( 2, 5- difluorophenyl

butanoyl-5,6,7,8-tetrahydroimidazo["1,2-a]pyrazine

The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-5|pyrazine (277 mg, 1.45 mmol, from Example 1, Step B), (3/i)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 416 mg, 1.32 mmol), DIPEA (226 mg, 1.58 mol), HOBT (216 mg, 1.98 mol) and HATU (753 mg, 1.98 mol) in DMF (6 mL), using a procedure analogous to that described in Example 1, Step C, with the exception of the purification procedure. The compound was purified by preparative TLC (silica gel, 20% hexane in ethyl acetate, then 10% methanol in dichloromethane) to give 360 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) 51.35 (s, 9H), 2.62 (m, 2H), 2.88 (m, 2H), 3.88-4.16 (m, 5H), 4.73 (s, 1H), 4.85 (m, 1H), 5.26-5.39 (m, 1H), 6.90 (bs, 1H), 7.06 (m, 2H), 7.24 (m, 1H). ESI-MS 489 (M+1).

Step B. 7-[( 3/^- 3- aminoQ- 4-( 2, 5- difluorophenyl) butanoyl- 5, 6, 7, 8- tetrahydro-

imidazofl, 2-alpyrazine, dihydrochloride

The title compound was prepared from 7-[(3/£i)-3-[(1,1-dimethyl-ethoxy!carbonyl)-amino]-4-(2;5-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-aJpyrazine (349.8 mg, 0.72 mol, from Step A) in 1.5 mL of methanol, saturated with hydrogen chloride, using a procedure analogous to that described in Example 1, Step D. Evaporation of the solvent afforded 299 mg of the title compound as a foamy solid. HNMR (500 MHz, CD3OD): δ 3.10-3.17 (m, 2H), 2.89-2.99 (m, 2H), 3.94-4.22 (m, 4H), 4.33 (m, 1H), 4.91-5.48 (m, 2H), 7.07-7.23 (m, 3H), 8.05 (m, 1H). ESI-MS 389 (M-r-1).

7-[(3/T)-3-amino-4-(2,4,5-irifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo, 2-alpyrazine, dihydrochloride

Step A. 7-f(3/i)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4l5-trifluorophenyl)

butanoyl1- 5, 6, 7, 8- tetrahydroimidazof1, 2- alpyrazine

The title compound was prepared from 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.7 mg, 0.166 mmol, from Example 1, Step B), (3/t)-3-[(1 t1 -dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 57 mg, 0.166 mmol). HOBT (26.9 mg, 0.199) mmol and EDC (47.8 mg, 0.249 mmol) in 4 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol in dichloromethane) afforded 40 mg of the title compound as a foamy solid. mass.<1>H NMR (500 MHz, CDCl3) 5 1.35 (s, 9H), 3.00 (m, 2H), 3.30 (m, 2H), 3.93 (m, 1H), 4.04-4.24 (m, 2H), 4.23 (s, 1H), 4.35 (m, 1H), 4.97-5.48 (m, 2H), 7.22 (m, 1H), 7.44 (m, 1H), 8.04 (m, 1H). ESI-MS 507 (M+1).

Step B. 7-[( 3/ 9 )- 3- amino- 4-( 2, 4, 5- trifluorophenyl) butanoyl- 5, 6, 7, 8- tetrahydro-

imidazofl, 2-alpyrazine, dihydrochloride

The title compound was prepared from 7-[(3/t)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl-5,6,7,8-tetrahydroimidazo[1,2-alpyrazine (38 mg, 0.075 mmol, from Step A) in 1.5 mL of methanol, saturated with hydrogen chloride, using a procedure analogous to that of described in Example 1, Step D. Evaporation of the solvent afforded 34 mg of the title compound as a foamy solid. (H NMR (500 MHz, CD3OD): δ 2.59-2.66 (m, 2H), 2.92 (m, 2H), 3.89-4.16-.4.22 (m, 5H), 4.70-4.84 (m, 2H), 5.42 (m, 1H), 6.86 (m, 1H), 7.06 (m, 1H), 7.24 (m, 1H).ESI-MS 407 (M+1).

7-|"( 3/^- 3- amino- 4-( 3, 4- difluorophenyl) butanoyl- 5, 6. 7. 8- tetrahydroimidazo1. 2- al

Pyrazine dihydrochloride

Step A. lmidazof1, 2- alpyrazine

To a solution of 2-aminopyrazine (2.0 g, 21.03 mmol) in ethanol (40 mL) was added 2-bromo-1,1-dimethoxyethane (2.5 mL, 21.03 mmol), followed by 5 drops of concentrated hydrochloric acid. After refluxing for 14 hours, the evaporated solvent. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3x). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (100% ethyl acetate, 10% methanol in ethyl acetate, then 10% methanol in dichloromethane) to give 536 mg of the title compound as a solid. J=4.4Hz), 8.10 (d, 1H, J=4.6Hz), 9.12 (S, 1H).

Step B. 5, 6, 7, 8- Tetrahydroimidazof1, 2- Alpyrazine

The title compound was prepared from imidazo[1,2-a]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration afforded the title compound (512 mg) as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 3.37 (t, 1H, J=5.5Hz), 4.18(t, 2H, J=5.6Hz), 4.88 (S, 1H), 7.27 (d, J=1.6Hz, 1H), 7.33 (d, 1H).

Step C. 7-|~( 3/ t)- 3-|"( 1 , 1- dimethylethoxycarbonyl) amino]- 4-( 3, 4- difluorophenyl)

butanoyl]- 5, 6, 7, 8- tetrahydroimidazo[ 1, 2- alpyrazine

The title compound was prepared from 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (31.3 mg, 0.254 mmol, from Step B), (3/t)-3-[(1 ,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (80 mg, mmol), DIPEA (32.8 mg, 0.254 mmol), HOBT (41.2 mg, 0.305 mmol) and EDC (73 mg, 0.381 mmol) in 5 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. Purification by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm I.D.; solvent gradient of 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid up to 90% acetonitrile, 10% water and 0.1% trifluoroacetic acid) gave 75 mg of the title compound as a viscous oil. <1>H NMR (500 MHz, CDCl3) 5 1.36 (S, 9H), 2.05 (bs, 1H), 2.62 (m, 2H), 2.89 (m, 2H), 3.81-4.04 (m, 5H), 4.64-4.88 (m, 2H), 5.38 (m, 1H), 6.88 (m, 2H), 7.05 (m, 3H). ESI-MS 421 (M+1).

Step D. 7-[( 3/ T )- 3- amino- 4-( 3, 4- difluorophenyl) butanoyl- 5, 6, 7, 8- tetrahydroimidazo[" 1, 2- aipyrazine, dihydrochloride

The title compound was prepared from 7-[(3/t)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (72 mg, 0.171 mmol, from Step C) in 1.5 mL of methanol, saturated with hydrogen chloride, using a procedure analogous to that of described in Example 1, Step D. Concentration afforded 66 mg of the title compound as a foamy solid. HNMR (500 MHz, CD3OD) 5 2.96-3.13 (m, 4H), 3.93 (m, 1H), 4.13 (m, 2H), 4.26-4.38 (m, 2H), 4.26-4.38 (m, 2H), 4.90-5.04 (m, 2H), 7.19-7.36 (m, 3H), 7.58 (m, 1H). ESI-MS 321 (M+1).

7- f( 3^- 3- amino- 4-( 3, 4- difluorophenyl) butanoi] 1- 3- ethyl- 5, 6, 7, 8- tetrahydro- 1, 2, 4-triazolo[ 4, 3- a1pyrazine, dihydrochloride

Step A. 8-Chloro-3-ethyl-1.2,4-triazoloph4,3-a~lpyrazine

To 3-chloro-2-hydrazinopyrazine (3.0 g, 20.75 mmol), which was prepared from 2,3-dichloropyrazine and hydrazine, using a procedure analogous to that described in the literature (Huynh-Dinh et al., J. Org. Chem. 1979, 44, 1028) was added 8 mL of triethyl orthopropionate. After refluxing for 10 h, the reaction mixture was cooled to ambient temperature and the precipitate was filtered. The solid was purified by flash chromatography (100% ethyl acetate followed by 10% methanol in ethyl acetate) to give 2.73 g of the title compound as a solid. <1>H NMR (500 MHz, CDCl3) 8 1.54 (t, 3H, J=7.6Hz), 3.16 (q, 2H, J=7.8Hz), 7.70 (d, 1H, J=4.5Hz), 7.83 (d. 1H, J=4.8Hz).

Step B. 3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolof4,3-alpyrazine, hydrochloride

The title compound was prepared from 8-chloro-3-ethyl-1,2,4-triazolo[4,3-β]pyrazine (2.70 g, 14.8 mmol, Step A) and platinum oxide (0.4

g) in 200 mL of methanol in a paar shaker, under hydrogen (50 psi), for 14 hours. Filtration through celite and then concentration gave

the title compound as a solid. 1H NMR (500 MHz, CD3OD) δ 1.36 (t, 3H, J=6.0Hz), 2.84 (q, 2H, J=6.0Hz), 3.70 (t, 2H, J=8.0Hz), 4.28 (t, 2H, J=8.0Hz), 4.06 (S, 2H). ESI-MS 153 (M+1).

Step C. 7 -\{ 3R )- 3 -\{ 1, 1 - dimethylethoxycarbonyl) amino1- 4-( 3, 4- difluorophenyl)

butanoyl]- 3- ethyl- 5, 6, 7, 8- tetrahydro- 1, 2, 4- triazolo[ 4, 3- alpyrazine

The title compound was prepared from 3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (400 mg, 2.12 mmol, from Step B), (3/t)-3-[(1,1-dimethylethoxycarbonyl)aminoj-4-(3,4-difluorophenyl)butanoic acid (668 mg, 2.12 mmol), DIPEA (1.1 mL, 4.24 mmol), HOBT (343.8 mg, 2.54 mmol), and EDC (609.6 mg, 3.18 mmol) in 20 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. The crude product was purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100 x 20 mm I.D.; solvent gradient). of 10% acetonitrile, 90% water and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water and 0.% trifluoroacetic acid) to give 366.3 mg of the title compound of Viscous Ui. 1H NMR (500 MHz, CDCl 3 ) δ 1.31-1.34 (m, 12H), 2.67-2.92 (m, 6H), 4.03-4.12 (m, 4H), 5.03-5.31 (m, 3H), 6.93 (s, 1H), 7.05 (m, 2H). ESI-MS 450 (M+1).

Step D. 7-[( 3/^- 3- amino- 4-( 3, 4- difluorophenyl) butanoyl- 3- ethyl- 5, 6, 7, 8-tetrahydro- 1, 2, 4- triazolo[ 4, 3- a ] pyrazine, dihydrochloride

The title compound was prepared from 7-[(3/^)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(3,4-difluorophenyl)butanoyl-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (30 mg, 0.067 mmol from Step C) in 1.5 mL of methanol, saturated with hydrogen chloride, using procedure, analogous to that described in Example 1, Step D. Evaporation of the solvent afforded 28 mg of the title compound as a viscous oil.<1>H NMR (500 MHz, CD3OD) 5 1.45 (t, 3H), 2.93-3.07 (m, 6H), 3.90-4.31 (m, 5H), 5.08 (m, 2H), 7.16 (s, 1H), 7.31 (m, 2H). ESI-MS 350 (M+H).

7- f( 3/^- 3- amino- 4-( 2, 5- difluorophenyl) butanoyl- 3-( trifluoromethyl)- 5, 6, 7, 8- tetrahydro- 1, 2, 4- triazolo|" 4, 3- a] pyrazine, hydrochloride

Step A. 3-(trifluoromethyl)-1,2,4-triazolo[4,3-alpyrazine

A mixture of 2-hydrazinopyrazine (820 mg, 7.45 mmol), which was prepared from 2-chloropyrazine and hydrazine, using a procedure analogous to that described in the literature (P.J. Nelson and K.T. Potts, J. Org. Chem. 1962, 27, 3243), except that the crude product was extracted into 10% methanol/dichloromethane and filtered, and the filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 100% ethyl acetate and then 10% methanol in dichloromethane), TFA (2.55 g, 22.4 mmol) and polyphosphoric acid (10 mL) was heated to 140°C, with stirring for 18 h. The solution was added to ice and neutralized with ammonium hydroxide. The aqueous layer was extracted with ethyl acetate (3X), washed with brine and dried over magnesium sulfate. Concentration followed by flash chromatography (silica gel, 1:hexane:ethyl acetate, then 100% ethyl acetate) afforded the title compound as a solid (861 mg).<1>H NMR (500 MHz, CDCl3) δ 8.17-8.20 (m. 2H), 9.54 (s, 1H). LC/MS (M+1) 189.

Step B. 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo"4,3-a]pyrazine

3-(Trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine (540 mg, 2.87 mmol, from Step A) was hydrogenated, under atmospheric hydrogen, with 10% Pd/C (200 mg) as catalyst, in ethanol (10 mL) at ambient temperature for 18 h. Filtration through celite and then concentration gave a dark colored oil. Dichloromethane was added to the upper oil, and the insoluble black precipitate was filtered off. Concentration of the filtrate gave the title compound as an oil (495 mg). 1H NMR (500MHz, CDCl 3 ) 52.21 (br, 1H), 3.29 (t, 2H, J=5.5 Hz), 4.09 (t, 2H, J=5.5Hz), 4.24 (s, 2H). LC/MS (M+1) 193.

Step C. 7 -\( 3R )- 3 -\( 1, 1 - dimethylethoxycarbonyl) aminol- 4-( 2, 5- difluorophenyl)

butanoyl- 3-( trifluoromethyl)- 5, 6, 7, 8- tetrahydro- 1, 2, 4- triazolof4, 3- alpira2in

The title compound was prepared from (3/t)-3-[(1 .1 -dimethylethoxycarbonyl()-amino]-4-(2,5-difluorophenyl)butanoic acid (Intermediate 1, 50 mg, 0.16 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (30 mg, 0.16 mmol), using procedure, analogous to that described in Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate, then 10% methanol/dichloromethane (2X)) to give the title compound (38.1 mg) as a solid. 2.57-3.05 (m, 4H), 3.85-4.30 (m, 5H), 4.90 (S, 1H), 4.95-5.15 (m, 1H), 5.22-5.40 (br, 1H), 6.86-7.24 (m, 3H). LC/MS (M+1-t-Boc) 390.

Step D. 7-[(3^)-3-amino-4-(2,5-difluorophenyl)butanoyl1-3-(trifluoromethyl)~

5, 6, 7, 8- tetrahydro- 1, 2, 4- triazoloph4, 3- alpyrazine, hydrochloride

The title compound was prepared from 7-[(3yc5)-3-[(1)1-dimethylethoxycarbonyl)-amino]-4-(2,5-difluorophenyl)butanoyl]-3-(trifluoromethyl)-'5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (19.1 mg, 0.039 mmol, from Step C), using a procedure analogous to that described for Example 1, Step D. Concentration afforded the title compound (16.1 mg) as a solid. 1H NMR (500 MHz, CD3OD) δ 2.75-3.16 (m, 4H), 3.86-4.35 (m, 5H), 4.95-5.05 (m, 2H), 7.03-7.20 (m, 3H). LC/MS (M+1) 390.

7- r( 3^- 3- amino- 4-( 2, 4, 5- trifluorophenyl) butanoin- 3-( trifluoromethyl)- 5, 6, 7, 8- tetrahydro- 1, 2, 4- triazolo|" 4, 3- alpyrazine, hydrochloride

Step A. 7-[( 3/^- 3-[( 1, 1- dimethylethoxycarboryyl) amino]- 4-( 2, 4, 5- trifluorophenyl)-butanoylT" 3-( trifluoromethyl)- 5, 67, 8- tetrahydro- 1, 2, 4- triazolof4, 3-alpyrazine

The title compound was prepared from (3β)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3, 50.1 mg, 0.15 mmol) and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (39.2 mg, 0.20 mmol), using procedure analogous to that described for Example 1, Step C. The crude product was purified by preparative TLC (silica gel, 100% ethyl acetate) to afford the title compound (29 mg) as a solid. 1H NMR (500 MHz, CDCl3) δ 1.37 (S, 9H), 2.61-3.00 (m, 4H), 3.92-4.30 (m, 5H), 4.93 (S, 1H), 4.95-5.12 (m,

1H), 5.22-5.35 (br, 1H), 6.83-6.95 (m, 1H), 7.02-7.12 (m, 1H). LC/MS (M+1-t-Bu) 452.

Step B. 7- ff3/ q)- 3- amino- 4-( 2, 4. 5- trif] fluoropheninbutanoyl- 3-( trifluoromethyl)-5, 6, 7, 8- tetrahydro- 1, 2, 4- triazolof4, 3- a1pyrazine, hydrochloride

The title compound was prepared from 7-[(3/t)-3-[(1,1-dimethylethoxycarbonyl)-amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (22 mg, 0.039 mmol, from Step A), using a procedure analogous to that described for Example 1, Step D. Concentration afforded the title compound (16.5 mg) as a solid. <1>H NMR (500 MHz, CD3OD) § 2.75-3.15 (m,4H), 3.82-4.35 (m, 5H), 4.90-5.05 (m, 2H), 7.16-7.25 (m, 1H), 7.30-7.42 (m, 1H). LC/MS (M+1) 408.

Following essentially the procedures set forth for Examples 1-7, the compounds listed in Table 1 were prepared.

While the invention has been described and illustrated with reference to certain specific embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, omissions or additions to the procedures and protocols can be made without departing from the spirit and scope of the invention. For example, effective dosages that differ from the specific dosages set forth hereinabove may be applicable due to variations in the response of a mammal treated for any of the indications with the compounds of the foregoing invention. The specific pharmacological responses observed may vary according to and depending on the particular active compounds selected and with regard to whether pharmaceutical carriers are present, as well as with regard to the type of formulation and route of administration used, and such expected variations or differences in results are considered in accordance with the objectives and practical application of the present invention. It was intended, however, that the invention be defined by the scope of the patent claims, which follow, and that such patent claims be interpreted with reasonable latitude.

Claims (30)

1. Compound of formula I: characterized in that: Ar is phenyl which is unsubstituted or substituted with 1-5 R<3>, wherein R<3> is independently selected from the group consisting of: (1) halogen, (2) C 1-6 alkyl, which is linear or garnet and unsubstituted or substituted with 1-5 halogens, (3) OC 1-6 alkyl, which is linear or garnet and unsubstituted or substituted with 1-5 halogens, and (4) CN; X is selected from the group consisting of: (1) N,i (2) CR<2>; R 1 and R 2 are independently selected from the group consisting of: (1) hydrogen, (2) CN, (3) Ci_ioalk.yl, which is linear or garnet and which is unsubstituted or substituted with 1-5 halogens, or phenyl, which is unsubstituted or substituted with 1-5 substituents independently selected from halogens, CN, OH, R<4>, OR<4>, NHS02R<4>, SO2R<4>, CO2H and CO2C,.6alkyl, wherein C02C]-6 alkyl linear or garnet, (4) phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from halogen, CN, OH, R<4>, OR<4>, NHS02R<4>, SO2R<4>, CO2H and C02C,.6alkyl, wherein C02C,_ 6alkyl is linear or garnet, and (5) 5- or 6-membered heterocycle. which can be saturated or unsaturated and which contains 1-4 heteroatoms independently selected from N, S and O, wherein the heterocycle is unsubstituted or substituted with 1-3 substituents independently selected from oxo, OH, halogen, Ci-alkyl and OCi-alkyl, wherein Ci-alkyl and OCi-alkyl are linear or branched and optionally substituted with 1-5 halogens; R 4 is C 1-6 alkyl, which is linear or garnet and which is unsubstituted or substituted with 1-5 groups independently selected from halogen, CO 2 H and C 1-6 alkyl, wherein CO 2 C 1-6 alkyl is linear or garnet; and pharmaceutically acceptable salts and individual diastereomers thereof. 2. Compound according to claim 1 of formula Ia: characterized in that X, Ar and R<1> are as defined in claim 1; and pharmaceutically acceptable salts and individual diastereomers thereof. 3. Compound according to claim 1 of formula lb: characterized in that Ar and R<1> are as defined in claim 1; and pharmaceutically acceptable salts and individual diastereomers thereof. 4. Compound according to claim 1 of formula Ic: characterized in that Ar, R<1> and R<2> are as defined in claim 1; and pharmaceutically acceptable salts and individual diastereomers thereof. 5. A compound according to any one of claims 1 to 4, characterized in that Ar is phenyl which is unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of: (1) fluoro, (2) bromo and (3) CF3. 6. Compound according to claim 5, characterized in that Ar is selected from the group consisting of: (1) phenyl, (2) 2-fluorophenyl, (3) 3,4-difluorophenyl, (4) 2,5-difluorophenyl, (5) 2,4,5-trifluorophenyl, (6) 2-fluoro-4-(trifluoromethyl)phenyl and (7) 4-bromo-2,5-difluorophenyl. 7. A compound according to any one of claims 1 to 6, characterized in that R<1> is selected from the group consisting of: (1) hydrogen and (2) C1-6 alkyl, which is linear or garnet and which is unsubstituted or substituted with phenyl or 1-5 fluoro. 8. Compound according to claim 7, characterized in that R<1> is selected from the group consisting of: (1) hydrogen, (2) methyl, (3) ethyl, (4) CF3, (5) CH2CF3, (5) CF2CF3, (6) phenyl and (7) benzyl. 9. A compound according to claim 8, characterized in that R<1> is selected from the group consisting of: (1) hydrogen, (2) methyl, (3) ethyl, (4) CF3 and (5) CH2CF3. 10. A compound according to claim 9, characterized in that R<1> is hydrogen or CF3. 11. A compound according to any one of claims 1 to 10, characterized in that R" is selected from the following: (1) hydrogen, (2) C 1-6 alkyl, which is linear or garnet and which is unsubstituted or substituted with 1-5 fluoro, and (3) phenyl, which is unsubstituted or substituted with 1-3 substituents independently selected from fluoro, OCI 13 and OCF 3 . 12. A compound according to claim 11, characterized in that R<2> is selected from the group consisting of: (1) hydrogen, (2) methyl, (3) ethyl, (4) CF3, (5) CH2CF3, (5) CF2CF3, (6) phenyl, (7) (4-methoxy)phenyl, (8) (4-trifluoromethoxy)phenyl, (9) 4-fluorophenyl and (10) 3,4-difluorophenyl. 13. A compound according to claim 12, characterized in that R is equal to CF 3 or CF 2 CF 3 . 14. A compound according to any one of claims 1 to 13, characterized in that R<3> is equal to F, Br or CF3. 15. A compound characterized by being selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 16. A pharmaceutical composition characterized by containing an inert carrier and a compound according to any of claims 1 to 15 or a pharmaceutically acceptable salt thereof. 17. A compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt for use in inhibiting dipeptidyl peptidase IV enzyme activity. 18. Use of a compound according to any of claims 1 to 15 or a pharmaceutically acceptable salt thereof for the production of a drug for the treatment, control or prevention of diabetes, non-insulin-dependent diabetes mellitus (type 2). hyperglycemia, obesity. insulin resistance, one or more lipid disorders selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL, atherosclerosis, one or more disorders selected from the group consisting of neutropenia, neuronal disorders, tumor metastasis, benign prostatic hypertrophy, gingivitis, hypertension, and osteoporosis, or one or more conditions selected from the group consisting of intestinal injury, inflammatory bowel disease, Crohn's disease, and ulcerative colitis. 19. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for the production of a drug for the treatment, control or prevention of one or more conditions selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its consequences, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) syndrome X, (24) ovarian hyperandrogenism (polycystic ovary syndrome), and other disorders whose component is insulin resistance. 20. A combination of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, and one or more other compounds selected from the group consisting of: (a) other dipeptidyl peptidase IV (DP-IV) inhibitors, (b) substances that increase insulin sensitivity selected from the group consisting of (i) PPAR agonists, (ii) biguanides and (iii) protein tyrosine phosphatase 1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylureas or other insulin secretagogues; (e) α-glucosidase inhibitors; (f) glucagon receptor agonists; (g) GLP-1, GLP-1 mimetics and GLP-1 receptor agonists; (h) GIP, GIP mimetics and GIP receptor agonists; (i) PACAP, PACAP mimetics and PACAP receptor 3 agonists; 0) cholesterol-lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors. (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or its salt, (iv) PPARa agonists, (v) PPARa/y dual agonists, (vi) cholesterol absorption inhibitors, (vii) acyl CoA cholesterol acyltransferase inhibitors and (viii) antioxidants; (k) PPAR5 agonists; (1) anti-obesity compounds; (m) ileal bile acid transporter inhibitor; and (n) anti-inflammatory agents. 21. A combination of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and an HMG-CoA reductase inhibitor. 22. Combination according to claim 21, characterized in that the HMG-CoA reductase inhibitor is a statin. 23. Combination according to patent claim 22, characterized in that the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin. fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin. 24. A pharmaceutical composition for the treatment, prevention or control of atherosclerosis, comprising: (1) a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, (2) an HMG-CoA reductase inhibitor and (3) a pharmaceutically acceptable carrier. 25. A pharmaceutical composition characterized by containing (1) a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof; (2) one or more compounds selected from the group consisting of: (a) other dipeptidyl peptidase IV (DP IV) inhibitors; (b) insulin sensitizing agents selected from the group consisting of (i) PPARy agonists, other PPAR ligands, PPARa/y dual agonists and PPARa agonists, (ii) biguanides, and (iii) protein tyrosine phosphatase 1B (PTP-1B) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylureas or other insulin secretagogues: (e) α-glucosidase inhibitors; (f) glucagon receptor agonists; (g) GLP-1, GLP-1 mimetics and GLP-1 receptor agonists; (h) GIP, GIP mimetics and GIP receptor agonists; (i) PACAP, PACAP mimetics and PACAP receptor 3 agonists; (j) cholesterol-lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants. (iii) nicotinyl alcohol, nicotinic acid or its salt, (iv) PPARa agonists, (v) PPARa/y dual agonists, (vi) cholesterol absorption inhibitors, (vii) acyl CoA cholesterol acyltransferase inhibitors and (viii) antioxidants; (k) PPAR5 agonists; (1) anti-obesity compounds; (m) ileal bile acid transporter inhibitor; and (n) anti-inflammatory agents; and (3) a pharmaceutically acceptable carrier. 26. A compound according to claim 15, characterized in that it is selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 26, characterized in that the compound is the following or a pharmaceutically acceptable salt thereof. 28. A compound according to claim 26, characterized in that it is a compound next or a pharmaceutically acceptable salt thereof. 29. A compound according to claim 26, characterized in that it is a compound next or a pharmaceutically acceptable salt thereof. 30. Pharmaceutical composition according to claim 25, characterized in that it contains a compound according to any of claims 1 to 15 or its pharmaceutically acceptable salt, netformin, and a pharmaceutically acceptable carrier.